The anthracycline anti-cancer drugs are intensely usedin the clinicto treat a wide variety of cancers. They generate DNA double strandbreaks, but recently the induction of chromatin damage was... Show moreThe anthracycline anti-cancer drugs are intensely usedin the clinicto treat a wide variety of cancers. They generate DNA double strandbreaks, but recently the induction of chromatin damage was introducedas another major determinant of anti-cancer activity. The combinationof these two events results in their reported side effects. Whileour knowledge on the structure-activity relationship of anthracyclineshas improved, many structural variations remain poorly explored. Therefore,we here report on the preparation of a diverse set of anthracyclineswith variations within the sugar moiety, amine alkylation pattern,saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human cancer cell lines, and the capacityto induce DNA- and chromatin damage. This coherent set of data allowedus to deduce a few guidelines on anthracycline design, as well asdiscover novel, highly potent anthracyclines that may be better toleratedby patients. Show less
Gelder, M.A. van; Zanden, S.Y. van der; Vriends, M.B.L.; Wagensveld, R.A.; Marel, G.A. van der; Codee, J.D.C.; ... ; Neefjes, J.J.C. 2023
The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was... Show moreThe anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure–activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients. Show less
Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of... Show moreAnthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase II alpha poisoning) and chromatin damage (via eviction of histones). These biological activities can be modulated and toxic side effects can be reduced by separating these two modes of action through alteration of the aminoglycoside moiety of doxorubicin. We herein report on the design, synthesis, and evaluation of a coherent set of configurational doxorubicin analogues featuring all possible stereoisomers of the 1,2-amino-alcohol characteristic for the doxorubicin 3-amino-2,3-dideoxyfucoside, each in nonsubstituted and N,N-dimethylated forms. The set of doxorubicin analogues was synthesized using appropriately protected 2,3,6-dideoxy-3-amino glycosyl donors, equipped with an alkynylbenzoate anomeric leaving group, and the doxorubicin aglycon acceptor. The majority of these glycosylations proceeded in a highly stereoselective manner to provide the desired axial alpha-linkage. We show that both stereochemistry of the 3-amine carbon and N-substitution state are critical for anthracycline cytotoxicity and generally improve cellular uptake. N,N-Dimethylepirubicin is identified as the most potent anthracycline that does not induce DNA damage while remaining cytotoxic. Show less
